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JAC Advance Access published online on June 2, 2009
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkp197
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Original research

In vitro activity of the β-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases

Thérèse Stachyra, Premavathy Levasseur, Marie-Claude Péchereau, Anne-Marie Girard, Monique Claudon, Christine Miossec* and Michael T. Black

Novexel SA, Parc Biocitech, 102 avenue Gaston Roussel, 93230 Romainville, France

Received 7 April 2009; returned 29 April 2009; revised 5 May 2009; accepted 7 May 2009

* Corresponding author. Tel: +33-1-5714-0747; Fax: +33-1-5714-0725; E-mail: christine.miossec{at}novexel.com

Background: NXL104 is a novel-structure β-lactamase inhibitor with potent activity against both class A and class C enzymes. Among the class A carbapenemases, KPC-type enzymes are now spreading rapidly and KPC-related carbapenemase resistance is an emerging phenomenon of great clinical importance. The activity of NXL104 against KPC β-lactamases was examined.

Methods: Enzymatic activity of purified recombinant KPC-2 was measured with nitrocefin as reporter substrate and inhibition by NXL104 was measured by determination of IC50 values. Antimicrobial susceptibility testing of various β-lactams combined with a fixed concentration of NXL104 at 4 mg/L against strains producing KPC enzymes was performed by the broth microdilution method.

Results: NXL104 was a potent inhibitor of KPC-2 with an IC50 of 38 nM. NXL104 restored the antimicrobial activity of ceftazidime, ceftriaxone, imipenem and piperacillin against Enterobacteriaceae strains producing KPC-2 or KPC-3. MIC values of ceftazidime against KPC producers were reduced by up to 1000-fold by combination with NXL104.

Conclusions: NXL104 inhibitory activity is unique in terms of spectrum, encompassing class A extended-spectrum β-lactamases, class C enzymes and class A carbapenemases. Given the limited therapeutic options available for infections caused by multiresistant Enterobacteriaceae isolates, NXL104 β-lactamase inhibitor is a promising agent to be used in combination with a β-lactam to protect its antibacterial activity.

Key Words: β-lactamase , carbapenem resistance , KPC inhibition


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